tbuckley/cabot-search huggingface dataset:
Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience
Authors: Bruno Fattizzo, Marta Bortolotti, Norma N. Fantini, Andreas Glenthøj, Marc Michel, Mariasanta Napolitano, Simona Raso, Frederick Chen, Vickie McDonald, Irina Murakhovskaya, Josephine Mathilde Iris Vos, Andrea Patriarca, Maria Eva Mingot-Castellano, Giulio Giordano, Margherita Scarrone, Tomás José González-López, Laura Trespidi, Daniele Prati, Wilma Barcellini
Journal: Blood (2023)

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb, 6.4 g/dL; range, 3.1-8.7) and required treatment in all cases (96% steroids ± intravenous immunoglobulin, IVIG, 58% transfusions). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.
A cell-based functional assay that accurately links genotype to phenotype in Familial HLH
Authors: Tahereh Noori, Jesse Alexander Rudd-Schmidt, Alisa Kane, Katie Frith, Paul E Gray, Hannah Hu, Danny Hsu, Clara W.T. Chung, Adrian W Hodel, Joseph A. Trapani, Ilia Voskoboinik
Journal: Blood (2023)
Factor XII contributes to thrombotic complications and vaso-occlusion in sickle cell disease
Authors: Erica M. Sparkenbaugh, Michael W. Henderson, Megan Miller-Awe, Christina Abrams, Anton Ilich, Fatima Trebak, Nirupama Ramadas, Shantel Vital, Dillon Bohinc, Kara L. Bane, Chunsheng Chen, Margi Patel, Michael Wallisch, Thomas Renné, Andras Gruber, Brian Cooley, David Gailani, Malgorzata Kasztan, Gregory M. Vercellotti, John D. Belcher, Felicity E. Gavins, Evi X. Stavrou, Nigel S. Key, Rafal Pawlinski
Journal: Blood (2023)
Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier
Authors: Kassandra Kisler, Abhay P. Sagare, Divna Lazic, Sam Bazzi, Erica Lawson, Ching-Ju Hsu, Yaoming Wang, Anita Ramanathan, Amy R. Nelson, Zhen Zhao, Berislav V. Zlokovic
Journal: Molecular Neurodegeneration (2023)

PICALM is one of the most significant susceptibility factors for Alzheimer's disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology.To identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm+/-) mice, Picalm+/-; 5XFAD mice and Picalmlox/lox; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior.Our screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm+/- mice by 2-3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm+/-; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34-51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm+/-; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects.Artesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.
Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease
Authors: Livius Penter, Yang Liu, Jacquelyn O. Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M. Cullen, Kathleen L. Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A. Morgan, Helen X. Chen, Minkyung H. Song, Magdalena Thurin, Shuqiang Li, Scott J. Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S. Neuberg, F. Stephen Hodi, Matthew S. Davids, Sacha Gnjatic, Kenneth J. Livak, Jennifer Altreuter, Franziska Michor, Robert J. Soiffer, Jacqueline S. Garcia, Catherine J. Wu
Journal: Blood (2023)

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.
COVID-19 severity by vaccination status in the NCI COVID-19 and Cancer Patients Study (NCCAPS)
Authors: Ana F Best, Melissa Bowman, Jessica Li, Grace E Mishkin, Andrea Denicoff, Marwa Shekfeh, Larry Rubinstein, Jeremy L Warner, Brian Rini, Larissa A Korde
Journal: JNCI Journal of the National Cancer Institute (2023)

We investigated the association of SARS CoV-2 vaccination with COVID-19 severity in a longitudinal study of adult cancer patients with COVID-19. A total of 1610 patients who were within 14 days of an initial positive SARS CoV-2 test and had received recent anticancer treatment or had a history of stem cell transplant or CAR-T cell therapy were enrolled between May 21, 2020, and February 1, 2022. Patients were considered fully vaccinated if they were 2 weeks past their second dose of mRNA vaccine (BNT162b2 or mRNA-1273) or a single dose of adenovirus vector vaccine (Ad26.COV2.S) at the time of positive SARS CoV-2 test. We defined severe COVID-19 disease as hospitalization for COVID-19 or death within 30 days. Vaccinated patients were significantly less likely to develop severe disease compared with those who were unvaccinated (odds ratio = 0.44, 95% confidence interval = 0.28 to 0.72, P < .001). These results support COVID-19 vaccination among cancer patients receiving active immunosuppressive treatment.
PD-1 blockade and lenalidomide combination therapy for chronic active Epstein-Barr virus infection
Authors: Yue Song, Jingshi Wang, Yini Wang, Lin Wu, Yahong You, Deli Song, Leilei Chen, Gaungqiang Meng, Xiaodan He, Tingting Cui, Xiaodi Wang, Qingxia Yin, Zhao Wang
Journal: Clinical Microbiology and Infection (2023)
Killing zombies: Senolytic therapy in pilocytic astrocytoma
Authors: Charles G Eberhart
Journal: Neuro-Oncology (2023)

Journal Article Killing zombies: Senolytic therapy in pilocytic astrocytoma Get access Charles G Eberhart Charles G Eberhart Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States Corresponding Author: Charles G. Eberhart, MD, PhD, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States (ceberha@jhmi.edu). Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 25, Issue 4, April 2023, Pages 748–749, https://doi.org/10.1093/neuonc/noad016 Published: 25 January 2023 Article history Published: 25 January 2023 Corrected and typeset: 02 February 2023
First-year recurrence rate of skin and soft tissue infections following an initial necrotizing soft tissue infection of the lower extremities: A retrospective cohort study of 93 patients
Authors: Hélène Traineau, Chloé Charpentier, Raphaël Lepeule, Saskia Ingen-Housz-Oro, Barbara Hersant, Tomas Urbina, Nicolas de Prost, Camille Hua, Olivier Chosidow
Journal: Journal of the American Academy of Dermatology (2023)
Clinical Images: Increased bone metabolism in secondary hyperparathyroidism
Authors: Larissa Valor‐Méndez, Armin Atzinger, Petra Reis, Bernhard Manger, Georg Schett
Journal: Arthritis & Rheumatology (2023)

The patient, a 47-year-old man, was diagnosed as having severe hyperparathyroidism secondary to end-stage kidney disease (ESKD), the underlying cause being leukocytoclastic vasculitis with IgA nephritis and minimal-change glomerulonephritis, which was confirmed by kidney biopsy in 2008. The patient had been receiving hemodialysis since 2014 and had a history of multiple fractures. His treatment included azathioprine, low-dose prednisolone, calcium carbonate, vitamin D, sevelamer, cinacalcet, torasemide, carvedilol, amlodipine, moxonidine, simvastatin, low molecular weight heparin, and erythropoietin. After a sudden transitory episode of vision loss with increased C-reactive protein (18.1 mg/liter) and response to glucocorticoids, 18F–positron emission tomography/computed tomography (18F-PET/CT) evaluation was performed to rule out systemic vasculitis. Ophthalmologic examination was negative for arteritic ischemic optic neuropathy, ophthalmoparesis, loss of visual field, and diplopia. Imaging with 18F-PET/CT revealed enhanced fluorodeoxyglucose uptake in the skeleton (A and B) and thickening of cortical bone such as in the femurs (C). Bone loss as osteolytic lesions in the calvaria, increased uptake in the setting of diffuse skull thickening with loss of distinction between the inner and outer table (D), and increased uptake in mandible bones (E) could be seen. There was no evidence for vasculitis. ESKD is associated with a complex remodeling of bone, summarized as renal osteopathy (1). This might include bone resorption, periosteal reaction, brown tumors, osteoporosis, osteosclerosis, osteomalacia, and soft tissue/vascular calcifications. Imaging may reveal any number of these conditions (2, 3). In our patient, 18F-PET/CT revealed osteolytic lesions, which were considered brown tumors and interpreted as osteitis fibrosa cystica. The patient was hypocalcemic (adjusted serum calcium 1.90 mmoles/liter), with elevated alkaline phosphatase (758 IU/liter) and massively elevated parathyroid hormone levels (1,872 pmoles/liter), indicating severe secondary hyperparathyroidism. These 18F-PET/CT images reflect the widespread, strongly induced metabolic activity of bone in secondary hyperparathyroidism during ESKD. Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Effect of switching from intermittently scanned to real-time continuous glucose monitoring in adults with type 1 diabetes: 24-month results from the randomised ALERTT1 trial
Authors: Margaretha M Visser, Sara Charleer, Steffen Fieuws, Christophe De Block, Robert Hilbrands, Liesbeth Van Huffel, Toon Maes, Gerd Vanhaverbeke, Eveline Dirinck, Nele Myngheer, Chris Vercammen, Frank Nobels, Bart Keymeulen, Chantal Mathieu, Pieter Gillard
Journal: The Lancet Diabetes & Endocrinology (2023)
Tingible body macrophages arise from lymph node–resident precursors and uptake B cells by dendrites
Authors: Neta Gurwicz, Liat Stoler-Barak, Niklas Schwan, Arnab Bandyopadhyay, Michael Meyer-Hermann, Ziv Shulman
Journal: The Journal of Experimental Medicine (2023)

Antibody affinity maturation depends on the formation of germinal centers (GCs) in lymph nodes. This process generates a massive number of apoptotic B cells, which are removed by a specialized subset of phagocytes, known as tingible body macrophages (TBMs). Although defects in these cells are associated with pathological conditions, the identity of their precursors and the dynamics of dying GC B cell disposal remained unknown. Here, we demonstrate that TBMs originate from pre-existing lymph node–resident precursors that enter the lymph node follicles in a GC-dependent manner. Intravital imaging shows that TBMs are stationary cells that selectively phagocytose GC B cells via highly dynamic protrusions and accommodate the final stages of B cell apoptosis. Cell-specific depletion and chimeric mouse models revealed that GC B cells drive TBM formation from bone marrow–derived precursors stationed within lymphoid organs prior to the immune challenge. Understanding TBM dynamics and function may explain the emergence of various antibody-mediated autoimmune conditions.
Development and Validation of a Deep Learning Algorithm to Differentiate Colon Carcinoma From Acute Diverticulitis in Computed Tomography Images
Authors: Sebastian Ziegelmayer, Stefan Reischl, Hannah Havrda, Joshua Gawlitza, Markus Graf, Nicolas Lenhart, Nadja Nehls, Tristan Lemke, Dirk Wilhelm, Fabian Lohöfer, Egon Burian, Philipp-Alexander Neumann, Marcus Makowski, Rickmer Braren
Journal: JAMA Network Open (2023)

Importance Differentiating between malignant and benign etiology in large-bowel wall thickening on computed tomography (CT) images can be a challenging task. Artificial intelligence (AI) support systems can improve the diagnostic accuracy of radiologists, as shown for a variety of imaging tasks. Improvements in diagnostic performance, in particular the reduction of false-negative findings, may be useful in patient care. Objective To develop and evaluate a deep learning algorithm able to differentiate colon carcinoma (CC) and acute diverticulitis (AD) on CT images and analyze the impact of the AI-support system in a reader study. Design, Setting, and Participants In this diagnostic study, patients who underwent surgery between July 1, 2005, and October 1, 2020, for CC or AD were included. Three-dimensional (3-D) bounding boxes including the diseased bowel segment and surrounding mesentery were manually delineated and used to develop a 3-D convolutional neural network (CNN). A reader study with 10 observers of different experience levels was conducted. Readers were asked to classify the testing cohort under reading room conditions, first without and then with algorithmic support. Main Outcomes and Measures To evaluate the diagnostic performance, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for all readers and reader groups with and without AI support. Metrics were compared using the McNemar test and relative and absolute predictive value comparisons. Results A total of 585 patients (AD: n = 267, CC: n = 318; mean [SD] age, 63.2 [13.4] years; 341 men [58.3%]) were included. The 3-D CNN reached a sensitivity of 83.3% (95% CI, 70.0%-96.6%) and specificity of 86.6% (95% CI, 74.5%-98.8%) for the test set, compared with the mean reader sensitivity of 77.6% (95% CI, 72.9%-82.3%) and specificity of 81.6% (95% CI, 77.2%-86.1%). The combined group of readers improved significantly with AI support from a sensitivity of 77.6% to 85.6% (95% CI, 81.3%-89.3%; P &amp;amp;lt; .001) and a specificity of 81.6% to 91.3% (95% CI, 88.1%-94.5%; P &amp;amp;lt; .001). Artificial intelligence support significantly reduced the number of false-negative and false-positive findings (NPV from 78.5% to 86.4% and PPV from 80.9% to 90.8%; P &amp;amp;lt; .001). Conclusions and Relevance The findings of this study suggest that a deep learning model able to distinguish CC and AD in CT images as a support system may significantly improve the diagnostic performance of radiologists, which may improve patient care.
Targeting Ara h 2 with human‐derived monoclonal antibodies prevents peanut‐induced anaphylaxis in mice
Authors: Marta Paolucci, Natascha Wuillemin, Valentine Homère, Dimitri Bieli, Alice Köhli, Barbara Ballmer‐Weber, Ying Waeckerle‐Men, Niccolò Pengo, Thomas M. Kündig, Tiziana Sonati, Pål Johansen
Journal: Allergy (2023)

Abstract Background Peanut allergy is a type‐I hypersensitivity immune reaction mediated by the binding of peanut allergens to IgE‐FcεRI complexes on mast cells and basophils and by their subsequent cellular degranulation. Of all major peanut allergens, Ara h 2 is considered the most anaphylactic. With few options but allergen avoidance, effective treatment of allergic patients is needed. Passive immunotherapy (herein called PIT) based on prophylactic administration of peanut‐specific monoclonal antibodies (mAbs) may present a promising treatment option for this under‐served disease. Method Fully human recombinant anti‐peanut IgG mAbs were tested in mice sensitized to peanut allergen extract. Allergic mice received intravenous immunotherapy with anti‐peanut Ara h 2‐specific IgG1 or IgG4 mAbs cocktails, and were then challenged by a systemic injection of high‐dose peanut allergen extract. The protection from allergic anaphylaxis was measured by monitoring the core body temperature. Results PIT with peanut‐specific mAbs was associated with a significant and dose‐dependent reduction of anaphylactic reactions in peanut‐sensitized mice challenged with peanut allergen extract. Complete protection was observed at doses approximately 0.3–0.6 mg mAbs. Mixtures of mAbs were more effective than single mAbs, and effective treatment could be obtained with mAbs of both IgG1 and IgG4 subclasses. The therapeutic effect of anti‐Ara h 2 mAbs was based on allergen neutralization and independent of the Fcγ receptor and mast‐cell inhibition. Conclusion This is the first report that shows that human‐derived anti‐peanut mAbs can prevent allergic anaphylaxis in mice. The study demonstrates that neutralizing allergenic epitopes on Ara h 2 by mAbs may represent a promising treatment option in peanut‐allergy.
Povetacicept, an Enhanced Dual <scp>APRIL</scp>/<scp>BAFF</scp> Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell–Related Autoimmune Diseases
Authors: Lawrence S. Evans, Katherine E. Lewis, Daniel DeMonte, Janhavi G. Bhandari, Logan B. Garrett, Joseph L. Kuijper, Daniel Ardourel, Martin F. Wolfson, Susan Debrot, Sherri Mudri, Kayla Kleist, Luana L. Griffin, LuAnne Hebb, Russell J. Sanderson, NingXin Wang, Michelle Seaberg, Allison G. Chunyk, Jing Yang, Youji Hong, Zahra Maria, David J. Messenheimer, Pamela M. Holland, Stanford L. Peng, Mark W. Rixon, Stacey R. Dillon
Journal: Arthritis & Rheumatology (2023)

Objective Dysregulated APRIL/BAFF signaling is implicated in the pathogenesis of multiple autoimmune diseases, including systemic lupus erythematosus and lupus nephritis. We undertook this study to develop and evaluate a high‐affinity APRIL/BAFF antagonist to overcome the clinical limitations of existing B cell inhibitors. Methods A variant of TACI‐Fc generated by directed evolution showed enhanced binding for both APRIL and BAFF and was designated povetacicept (ALPN‐303). Povetacicept was compared to wild‐type (WT) TACI‐Fc and related molecules in vitro and in vivo. Results Povetacicept inhibited APRIL and BAFF more effectively than all evaluated forms of WT TACI‐Fc and selective APRIL and BAFF inhibitors in cell‐based reporter assays and primary human B cell assays, mediating potent suppression of B cell proliferation, differentiation, and immunoglobulin (Ig) secretion. In mouse immunization models, povetacicept significantly reduced serum immunoglobulin titers and antibody‐secreting cells more effectively than anti‐CD20 monoclonal antibodies, WT TACI‐Fc, or APRIL and BAFF inhibitors. In the NZB × NZW mouse lupus nephritis model, povetacicept significantly enhanced survival and suppressed proteinuria, anti–double‐stranded DNA antibody titers, blood urea nitrogen, glomerulonephritis, and renal immunoglobulin deposition. In the bm12 mouse lupus model, povetacicept significantly reduced splenic plasmablasts, follicular helper T cells, and germinal center B cells. In non‐human primates, povetacicept was well tolerated, exhibited high serum exposure, and significantly decreased serum IgM, IgA, and IgG levels after a single dose. Conclusion Enhanced APRIL and BAFF inhibition by povetacicept led to greater inhibition of B cell populations critical for autoantibody production compared to WT TACI‐Fc and CD20‐, APRIL‐, or BAFF‐selective inhibitors. Potent, dual inhibition by povetacicept has the potential to significantly improve clinical outcomes in autoantibody‐related autoimmune diseases. image